Zika virus (ZIKV) emerged in the Americas in early 2015, causing millions of infections and affecting more than 40 countries and territories. The American ZIKV epidemic was the first time that ZIKV's teratogenic potential was recognized after Brazil experienced a surge in the incidence of newborn microcephaly linked to congenital ZIKV infection. While the link between congenital ZIKV infection and structural brain abnormalities is well established, the spectrum of developmental sequelae of congenital ZIKV infection findings is still not well described. Additionally, no data exists about the role of maternally acquired antibodies against ZIKV in the protection against (or risk for) flavivirus infections in early childhood. Due to the cross-reactivity of ZIKV and dengue virus (DENV) antibodies, there is the concern that decaying ZIKV antibodies may contribute to antibody-dependent enhancement of DENV infections. Characterizing the kinetics of maternally acquired antibodies against ZIKV is also crucial to inform schedules for ZIKV and DENV vaccines under development. Here, we propose to leverage an existing cohort of 400 pregnant women and their infants in Len, Nicaragua, where the ZIKV swept through the population in the second half of 2016. The women were pregnant during a period of intense ZIKV transmission, and we have collected prenatal maternal, cord blood, and quarterly postnatal serum samples, alongside longitudinal developmental data on the infants. We propose to extend follow up of children up to 36 months of age to better characterize the prevalence and spectrum of developmental abnormalities that occur after ZIKV exposure in utero and to measure duration of maternally derived neutralizing antibodies to ZIKV after birth. Neurodevelopmental outcomes will be evaluated with Mullen Scales of Early Learning at 3, 6, 12, 18, 24, 30, and 36 months. This tool assesses gross motor, fine motor, visual reception, expressive language, and receptive language domains. Vision and hearing will be formally assessed once during the study. ZIKV congenital exposure will be diagnosed using ZIKV and DENV IgM and IgG ELISA in maternal and cord blood samples; indeterminate results will be resolved using antibody depletion and focus reduction neutralizing tests for DENV and ZIKV. We hypothesize that infants with evidence of in utero exposure to ZIKV will display a range of developmental deficits and that the prevalence of deficits will be substantially higher in the ZIKV-exposed group than in unexposed infants. Additionally, we hypothesize that maternally acquired ZIKV immunity will wane over 2-9 months, similar to maternally acquired DENV antibodies. We will assess the effect of maternally acquired ZIKV antibodies on the incidence of DENV infections in the cohort. These findings will provide essential clinical data to characterize the types of developmental deficits resulting from congenital ZIKV infection, to direct early intervention efforts and will further our understanding of ZIKV immunity and its effect on DENV infection in early childhood, which are crucial to vaccine development and timing.

Public Health Relevance

An explosive epidemic of Zika virus (ZIKV) spread throughout South and Central America and the Caribbean from 2015-2017, revealing a previously unrecognized capacity of the flavivirus to cause severe neurological abnormalities in infants born to women infected during pregnancy; however, little is known about subtler health effects of maternal ZIKV infection on their children. We propose to 1) characterize the range of developmental outcomes of congenital Zika virus exposure in a population-based birth cohort with well-defined Zika virus exposure status, and 2) examine the rate of decay of maternally-acquired Zika-specific antibodies and their effect on dengue incidence in early childhood. We anticipate that the results of this study will elucidate the full spectrum of Zika virus-mediated neurodevelopmental injury and provide guidance for public health interventions including development of dengue and Zika vaccine schedules.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Esch, Thomas R
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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